Assistant Professor, Pharmacology and Toxicology
1355 BOGUE ST ROOM B440
EAST LANSING MI 48824
The overall aim of my research is to determine the mechanisms that modulate immune cell differentiation and function. Specifically, I am interested in the effects of xenobiotic sensors on the regulation of lymphocyte function. It is my overall hypothesis that, in general, xenobiotic sensors serve to limit lymphocyte response to reactive xenobiotics thus averting exaggerated or inappropriate immune responses that might otherwise cause autoimmunity or other types of inflammatory conditions. My current research focuses on the role of the stress-activated transcription factor, nuclear factor erythroid 2 related factor 2 (Nrf2), on T cell function and T cell-dependent immune responses.
Recent studies demonstrate that Nrf2 plays a critical cytoprotective role in countering oxidative and electrophilic cellular stresses. Nrf2 is activated by a variety of chemicals, including environmental contaminants such as arsenic, cadmium, cigarette smoke and diesel exhaust. In addition, several widely used food preservatives also activate Nrf2. Thus, Nrf2 activators are widely disseminated in the environment and in our food. Several recently-published papers describe the suppressive effects of Nrf2 in innate immunity. In addition, the development of lupus-like pathology in Nrf2-null mice suggests that Nrf2 also plays an important role in adaptive immunity, but the role of Nrf2 in regulating the function of T cells and other lymphocytes remains unclear.
Our published studies strongly suggest that activated Nrf2 modulates CD4 T cell differentiation (Rockwell et al., 2012). CD4 T cell differentiation is the process by which naïve, mature CD4 T cells adopt a specialized function which allows for a tailored immune response to a specific pathogen. Th1 cells specialize in host defense against intracellular pathogens and cell-mediated immunity, for instance. In contrast, Th2 cells are specialized to respond to large parasites, such as helminths and nematodes as well as in providing humoral immunity. While important in host defense, Th2 cells are also strongly implicated in the development of asthma and allergy.
Our data strongly suggest that activation of Nrf2 promotes Th2 differentiation and concurrently inhibits Th1 differentiation as evidenced by cytokine production and activity of transcription factors that regulate Th1/Th2 differentiation (GATA-3 and T-bet). One of the ongoing projects in the lab is to determine the molecular mechanisms by which this occurs. In addition, the effects of Nrf2 on CD4 T cell differentiation suggest that activation of Nrf2 could potentially impact immune response. Specifically, our data suggest that activation of Nrf2 by a robust activator, such as certain food preservatives (tBHQ), could potentially exacerbate allergic response. We are currently testing this hypothesis in a mouse model of food allergy. Conversely, these data also suggest that cell-mediated immune responses and host immunity to intracellular pathogens could be impaired by Nrf2 activators (such as, tBHQ, cadmium, arsenic). We are testing that hypothesis in a mouse influenza model of infectious disease.
University of Michigan, B.S., 1994, Biology
Michigan State University, Ph.D., 2005, Pharmacology & Toxicology
Selected Professional Activities:
American Association of Immunologists, 2001-Present
American Society for Pharmacology and Experimental Therapeutics, 2003-Present
Society of Toxicology, 2004-Present
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